SINGAPORE — Researchers from the National University Hospital (NUH), the Yong Loo Lin School of Medicine, National University of Singapore (NUS Medicine), National University Cancer Institute, Singapore (NCIS) and the Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), have found that a common genetic variant, when combined with metabolic factors such as diabetes and obesity, is associated with a significantly higher risk of liver cancer.
The findings come from a large, population‑based study involving nearly 25,000 participants from the Singapore Chinese Health Study, a cohort established since 1993 for research on cancer and other chronic diseases of importance in Singapore and worldwide. This specific study has been published in Alimentary Pharmacology & Therapeutics1, a leading international journal in gastroenterology.
This study is among the first large‑scale prospective analyses in Asia to demonstrate a clear, dose‑dependent relationship between the PNPLA3 I148M variant and liver cancer risk. This means that risk increases progressively with the number of risk gene copies carried. Individuals with two copies of the variant faced the highest risk.
Importantly, the researchers found that genetic risk does not act in isolation. Liver cancer risk increased when combined with common metabolic conditions.
Principal investigator Adj A/Prof Daniel Huang, Senior Consultant, Division of Gastroenterology and Hepatology, Department of Medicine, NUH and Chair of the Hepato-Pancreato-Biliary Cancer Programme at NCIS said: “Our findings show that diabetes and obesity effectively “stack” on top of genetic susceptibility to further increase liver cancer risk. This highlights the importance of considering genetic factors together with routinely available clinical information, rather than viewing them separately.” On the other hand, individuals with a higher genetic risk for liver cancer may be able to meaningfully reduce their risk by adopting a healthy lifestyle, particularly by preventing diabetes and maintaining a healthy weight.
Men who carried two copies of the PNPLA3 I148M variant had up to a nine‑fold higher risk of hepatocellular carcinoma (HCC), the most common form of primary liver cancer, compared with women who did not carry the variant. Elevated risks were also observed among carriers who were overweight or had diabetes, compared with non‑carriers without these conditions.
Notably, the genetic association appeared more prominent among individuals without chronic hepatitis B, underscoring its relevance as liver cancer increasingly arises from non‑viral causes, such as fatty liver disease and metabolic conditions.
According to the Singapore Cancer Registry Annual Report 2023, liver cancer was among the three leading contributors to cancer deaths in males between 2019 to 2023.
Liver cancer is often asymptomatic in its early stages, and many patients are diagnosed only when the disease is advanced, limiting treatment options.
With the rise of fatty liver disease as a major cause of liver cancer, these findings highlight how clinical factors – including sex, diabetes and obesity – can meaningfully influence risk when combined with genetic susceptibility.
The researchers noted that while genetic testing is not currently part of routine liver cancer screening, the findings suggest that combining genetic information with readily available clinical data may support more targeted, risk-based screening strategies in the future, helping identify individuals who may benefit from closer monitoring, including those who may not fall within traditional high-risk groups.
The importance of identifying individuals at higher risk and detecting disease early is illustrated by the experience of Mr Foo Say Nong, 74.
Mr Foo was first diagnosed with early‑stage liver cancer in 2018 after a routine follow‑up for fatty liver disease. He underwent minimally invasive surgery at NUH, and the tumour was successfully removed.
“I didn’t have any symptoms or pain at all. Without regular follow‑ups, it could easily have gone unnoticed,” Mr Foo said.
Seven years later, in 2025, Mr Foo volunteered to participate in a research study on genetics in liver cancer led by Adj A/Prof Huang. Advanced imaging performed as part of the study detected a new, unrelated liver tumour at an early stage. He underwent successful image‑guided ablation and is currently in remission.
Understanding the value of research in improving early detection, Mr Foo also encouraged family members to take part in the study.
Today, he is enjoying retirement, spending time with his grandchildren and practising meditation and qigong.
At the National University Health System (NUHS), the findings reflect ongoing efforts to translate population‑based research into insights that can inform future clinical practice. As liver cancer increasingly arises from metabolic and non‑viral causes, there is a growing need for more precise, risk‑stratified approaches to early detection.
By improving the understanding of how genetic and metabolic factors interact, such research contributes to NUHS’s broader commitment to advancing evidence‑based, patient‑centred care, with the long‑term goal of improving early diagnosis and outcomes.
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1 https://pubmed.ncbi.nlm.nih.gov/41527281/
